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NAD+ precursor supplementation in human ageing: clinical evidence and challenges

Nature Metabolism volume 7, pages 1974–1990 (2025)Cite this article

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Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in cellular metabolism, and its decline has been implicated in ageing and age-related disorders. However, evidence for an age-related decline in NAD+ levels in humans has been consistently observed only in a limited number of studies. Similarly, although preclinical studies support the idea that supplementation with NAD+ precursors is a promising therapeutic strategy to promote healthy ageing, human clinical trials have shown limited efficacy. Therefore, an increasing understanding of how NAD+ metabolism is affected in different tissues during disease and following NAD+ precursor supplementation is crucial to defining the therapeutic value of NAD+-targeted therapies. In this Review, we evaluate the clinical evidence supporting the notion that NAD+ levels decline with age, as well as the tissue-specific effects of NAD+ precursor supplementation. Viewed in perspective, the published body of data on NAD+ dynamics in human tissues remains sparse, and the extrapolation of rodent-based data is not straightforward, underscoring the need for more clinical studies to gain deeper insights into systemic and tissue-specific NAD+ metabolism.

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Fig. 1: Alterations in NAD+ levels across human tissues during ageing and in response to precursor supplementation.
Fig. 2: Central metabolic pathways related to NAD+.
Fig. 3: Metabolic fate of orally administered NAD+ precursors.
Fig. 4: Age-driven tissue-specific changes in NAD+ abundance.

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Acknowledgements

The authors gratefully acknowledge the contributions of the NADIS consortium members: F.L. Bertoli (Institut Imagine Paris, France), R.P. Mato (Università degli Studi di Genova, Italy), T. Brochard (University of Oulu, Finland), J. Frank (University of Oslo, Norway), F. Matiyevskaya (University of Copenhagen, Denmark), M.E. Ermert (Khondrion BV, Nijmegen; Amsterdam UMC, Netherlands), Q. Zhang (University of Copenhagen, Denmark), L. Van Gijn (École Polytechnique Fédérale de Lausanne, Switzerland), S. Bruzzone (Università degli Studi di Genova, Italy), M. Deleidi (Institut Imagine Paris, France), M. Scheibye-Knudsen (University of Copenhagen, Denmark), E.F. Fang (University of Oslo, Norway), E. Pirinen (University of Oulu, Finland), H. Renkema (Khondrion BV, Nijmegen, Netherlands) and J. Smeitink (Khondrion BV, Nijmegen, Netherlands). K.T.V., M.M.T., C.C., G.E.J. and R.H.H. received funding from the European Union’s Horizon Europe research and innovation programme through the NADIS project (#101073251). R.Z.-P. is supported by a project (PID2023-147560OA-I00) from the Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación and by the Fondo Europeo de Desarrollo Regional (FEDER, EU).

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Author notes

  1. These authors contributed equally: Kasper T. Vinten, Maria M. Trętowicz.

Authors and Affiliations

  1. Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

    Kasper T. Vinten, Maria M. Trętowicz, Evrim Coskun, Michel van Weeghel, Georges E. Janssens & Riekelt H. Houtkooper

  2. Amsterdam Gastroenterology, Endocrinology and Metabolism Institute, Amsterdam UMC, Amsterdam, the Netherlands

    Kasper T. Vinten, Maria M. Trętowicz, Georges E. Janssens & Riekelt H. Houtkooper

  3. Core Facility Metabolomics, Amsterdam, the Netherlands

    Michel van Weeghel

  4. Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Carles Cantó

  5. Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Carles Cantó

  6. Group of Metabolism and Gene Regulation, UCAM HiTech Sport & Health Innovation Hub, Universidad Católica de Murcia, Murcia, Spain

    Rubén Zapata-Pérez

  7. Amsterdam Cardiovascular Sciences Institute, Amsterdam UMC, Amsterdam, the Netherlands

    Riekelt H. Houtkooper

  8. Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, the Netherlands

    Riekelt H. Houtkooper

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Contributions

K.T.V., M.M.T., C.C., R.Z.-P., G.E.J. and R.H.H. conceptualized the article. K.T.V. and M.M.T. wrote the manuscript, with contributions from all coauthors. K.T.V., M.M.T. and E.C. researched data and created the tables. M.v.W. provided substantial input on technical and methodological aspects. All authors reviewed, edited and approved the final version of the manuscript.

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Vinten, K.T., Trętowicz, M.M., Coskun, E. et al. NAD+ precursor supplementation in human ageing: clinical evidence and challenges. Nat Metab 7, 1974–1990 (2025). https://doi.org/10.1038/s42255-025-01387-7

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